Alzheimer's disease (AD) is a neurodegenerative disorder affecting Approximately 15% of the population over 65 years of age (˜12 million worldwide, 4 million in US, 0.4 million in Canada), and is the predominant cause of progressive intellectual and cognitive failure in the aging population. Given the shifting demographics of our population, the impact of AD on public health is predicted to rise at least three-fold in the next 50 years. The disease claims over 100,000 lives/year, making it the 4th leading cause of death in adults. As well, the cost of treatment and caring for these patients is estimated to be as high as $100 billion a year in the US alone. One of the hallmarks of AD is the accumulation of β-amyloid (Aβ) in the brain, particularly in senile plaques and cerebral microvessels. Although a number of proteins are associated with amyloid plaques, amyloid peptide (typically 39-43 aa in length) has been identified as the principal constituent of the plaque. A substantial body of evidence based on genetic, pathological and biochemical studies have indicated that Aβ plays a causal role in the development of AD pathology. A chronic imbalance in the production and clearance of Aβ results in its accumulation, either intra- or extra-cellularly, as amyloid, or other aggregated form. This gradual accumulation of aggregated Aβ initiates a cascade of events that include gliosis, inflammatory changes, neuritic/synaptic loss and transmitter loss, eventually leading to neuronal dysfunction and death.
Despite considerable progress in understanding the molecular mechanism of AD pathology, there are no effective drugs or treatments currently available that can prevent/cure the disease.
In AD, there is a severe loss of cholinergic neurons and consequently a decreased level of neurotransmitter acetylcholine (ACh) which is implicated in memory processing and storage. Therefore, cholinergic augmentation might improve cognition in AD. Indeed, the only FDA approved drugs for the treatment of AD are acetylcholine esterase (AChE) inhibitors that prevent the loss of ACh. However, the beneficial effects of this drug are limited, and the accompanying side-effects are problematic. The other treatments include the use of antioxidants such as vitamin E, non-steroidal anti-inflammatory drugs (NSAIDS), cholesterol-lowering drugs and estrogen therapy to mitigate the inflammatory effects of plaque formation and enhance neuroprotection. However, none of these treatments appear to have any long-term beneficial effects, particularly in improving cognition, behavior and function in AD patients. Clearly therefore, there is a great need for developing alternate approaches to identify potentially more effective drugs to treat AD.
The dynamic balance between the soluble and the insoluble pools of AD in the brain is regulated by increased production and by decreased clearance and/or increased uptake from the circulation. Therefore, agents that inhibit Aβ generation, inhibit its activity and/or promote its clearance have the potential to be more effective drugs to treat AD. The generation of Aβ from its precursor protein APP is achieved by sequential proteolysis of APP by proteases b and g secretases. Inhibitors of these enzymes have been shown to reduce Aβ production and are being developed as potential drugs for treating AD. Similarly agents that sequester and/or promote Aβ clearance are also being developed. Notable among these is the development of AD vaccine. Both active and passive immunization with Aβ has been shown to be effective in preventing Aβ deposition as well as clearing of preformed amyloid plaques in transgenic animal models of AD1-3. The principal mechanism of action of AD vaccines appears to be sequestration of circulatingAR.
As mentioned above, currently there is no clinically proven drug that can prevent or cure AD. The only FDA approved drugs that are in clinical use to treat AD are the acetylcholine esterase (AChE) inhibitors. AChE is an enzyme that controls communication between nerve cells by the neurotransmitter acetylcholine. This communication is disrupted by the death of nerve cells in AD patients, and inhibitors of AChE are approved as drugs to elevate acetylcholine and aid neuronal function in these patients. However, the effects of these therapies are transient, providing temporary changes in cognition and function and do not stop the progression of the disease. In addition, other limitations of these drugs are the severe side effects, such as nausea, diarrhea, vomiting and anorexia. Similarly, alternate treatments such as antioxidants, non-steroidal anti-inflammatory drugs (NSAIDS) and estrogen therapy also do not have any long term beneficial effects, particularly in improving cognition, behavior and function in AD patients.
Currently several novel approaches to treating AD are being studied. Inhibitors of b and g secretases that prevent proteolytic cleavage of APP giving rise to Aβ peptides are being developed. However, their therapeutic efficacy in reducing Aβ burden is not yet known. Moreover, since these enzymes are also involved in the processing of other enzymes and signaling molecules such as Notch that are linked to neuronal development, these inhibitors may have serious non-specific side effects.
β-amyloid deposits are believed to strongly stimulate inherent immune response in the brain which triggers progressive inflammation, neuronal loss, and further acceleration of senile plaque formation. Immunotherapeutic approaches such as AD vaccines have been shown to be quite effective in reducing Aβ deposition and partial elimination of memory deficits in transgenic animals1-3. In human trials, Aβ vaccination showed significant reduction in cortical Aβ deposition, slow progression of dementia and stabilization of cognition. However, clinical trials had to be abandoned due to severe inflammatory reactions (meningo-encephalitic presentation) observed in a small number of AD patients.